Malaria in Ethiopia Vivax malaria is the most geographically widespread human malaria, causing tremendous suffering and major negative effects on economic productivity. African blacks or people with African ancestry are thought to be protected from Plasmodium vivax infection because their lack of Duffy antigen expression on the surface of the erythrocytes renders P. vivax unable to invade the erythrocytes. However, recent studies challenge this conventional wisdom, raising the possibility that that some lineages of P. vivax may have evolved to use receptors other than Duffy for erythrocyte invasion. However, the epidemiological significance of vivax infection in Duffy-negative individuals is unknown. Furthermore, there is no information on the evolutionary history and infection diversity of P. vivax in Duffy-negative individuals. In this application, we propose to examine the molecular epidemiology and population genetics of P. vivax in a vivax endemic area in Ethiopia. The two specific aims are: 1) to determine the prevalence of asymptomatic infections and the incidence of symptomatic malaria due to P. vivax in Duffy-negative and Duffy-positive individuals in vivax endemic Ethiopia, and 2) to determine the evolutionary history and genetic diversity of P. vivax isolates from Duffy-negative people. By determining the prevalence of asymptomatic infections and incidence of symptomatic infections in Duffy-negative and -positive individuals, we will be able to assess the level of protection from vivax infection conferred by Duffy negativity. The findings from this study will have important implications on the vivax Duffy binding protein-based vaccine strategy against vivax infections, and significantly improve our understanding of vivax malaria distribution and transmission in a region of Africa that inhabited predominantly by Duffy-negative people. As our study sites have a large number of vivax cases, including many severe and cerebral cases and a large number of Duffy-negative individuals, they offer a unique opportunity to study the epidemiology and transmission of P. vivax in Africa.